Throughout this application, various publications are referenced by author and date. Full citations for these publications may be found listed alphabetically at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
One of the most important applications of computational chemistry is the prediction of the properties of new chemical compounds. If such predictions could be reliably made, then new materials or compounds having desirable properties could be designed rationally. Unfortunately, reliable property prediction is very difficult to achieve. One of the most sought after property predictions is found in the pharmaceutical industry. There, chemists often hypothesize dozens of molecules they might synthesize but have trouble deciding which ones have the best chance of being highly active in some biological assay.
Researchers have tried for many years to calculate the relative binding energies of closely related drug molecules for biological and chemical receptors using free energy perturbation or thermodynamic integration (Kollman, 1993). Such methods gradually mutate one drug into another over many (10-100) stages and such multistage methods are not only slow, but they have not proven to be truly predictive. Because of recent advances in molecular biology and x-ray crystallography, the three-dimensional molecular structures of many biological target proteins are now known. In theory, the knowledge of the structure of the target protein could be used to rationally design hypothetical molecules that strongly bind the target protein. Such molecules would then be candidates for actual chemical synthesis. Unfortunately, the calculations are quite complex from a thermodynamic standpoint. The current approaches to predictions of drug-protein binding energies are too inaccurate and too slow to be used for practical drug design. The invention described herein provides a solution to this problem.
The present invention provides for a method for selecting a molecule for a population which comprises: a) selecting a first molecule with a conformation characterized by a particular set of coordinates that define the position of each atom in the first molecule; b) determining the energy of the first molecule; c) transforming the coordinates of the first molecule to the coordinates of a second structurally distinct molecule to produce a particular conformation of the second molecule characterized by a particular set of coordinates that define the position of each atom in the second molecule; d) determining the energy of the second molecule; thus, selecting either the first molecule or the second molecule for the population based on their relative energies. The selected molecule may be redefined as the first molecule and the procedure repeated iteratively so as to obtain a population of first molecules and a population of second molecules. Based on the populations, the free energy difference between the first molecule and the second molecule may be determined.